Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-01-19
2001-06-05
Leary, Louise (Department: 1623)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S004000, C435S975000
Reexamination Certificate
active
06242197
ABSTRACT:
The present invention pertains to the use of the urinary trypsin inhibitor for the diagnosis of the onset of AIDS. In particular the present invention relates to the use of antibodies directed against said urinary trypsin inhibitor for the diagnosis of the onset of AIDS. In another embodiment of the invention the antibodies are provided in a kit for determining the onset of AIDS.
In the early 80's patients were observed in hospitals that had developed severe immunodeficiencies. Some of them developed unusual opportunistic infections while others have been found to suffer from Kaposi's sarcoma, a hitherto rare skin tumor. An immunologic evaluation of these patients showed a marked deficiency of the cellular immune function and a selective decrease of the number of T4 (helper) cells, a subpopulation of T cells that mediate the cellular immune response. This condition with all of its accompanied symptoms was termed “Acquired Immune Deficiency Syndrome” (AIDS). The disease itself was subsequently found to be caused by a pathogenic retrovirus called human immunodeficiency virus (HIV-virus).
Soon after HIV was found to be the origin of AIDS it was observed that this virus was in particular cytopathic for T4 cells. It was therefore hypothesized that the immunological abnormalities in AIDS resulted at least in part from a progressive depletion of T4 cells due to their infection and destruction by HIV.
From the clinical point of view the “disease” AIDS is defined as the presence of a reliably diagnosed disease at least moderately indicative of cellular immune deficiency with the absence of known underlying immune deficiency and of any other reduced resistance reported to be associated with the disease, such as e.g. immunosuppressive therapy or lymphoreticular malignancy.
The disease AIDS, that is the last stage of a slowly but constantly progressing decline of the body's normal constitution, is preceded by a variety of diseases that are generically designated as “predromal AIDS”. Such disorders include ARC (Aids Related Complex) which state of disease is considered to be highly predictive of the development of subsequent AIDS. ARC includes the symptoms of e.g. having fever for more than 3 months, exhibiting a loss of weight by more than 10%, suffering from diarrhoea and showing a reduced number of T4 cells. This state of disease is known to eventually develop into the so called LAIDS (Lesser AIDS) which state is characterized by the development of oral candidasis, herpes zoster, idiopathic thrombocytopenia and other diseases that are not lethal, do, however, indicate immune suppression.
Another predictive symptom for the prospective development of AIDS is the so called LAS (lymphadenopathy syndrome), which is identified by the presence of at least three or more lymph nodes outside of the regio inguinals having a diameter of more that 1 cm.
Yet, another indication for the coming development of AIDS is the ADC symptoms (AIDS dementia complex) which is seen in the increasing number of detrimental influences on brain activity.
With the progress of molecular biology and cell biology techniques the determination of various antigenic determinants of the HIV virus itself has become possible. To this end, antibodies have been prepared with which the presence of the virus in the blood of a patient can be detected. With these tests it is, however, merely possible to determine the presence or absence of an HIV infection while the imminent manifestation of the disease as such can not reliably be predicted thereby. Hence, due to the complex picture of the predromal disease states mentioned above it is often difficult for the physician to determine whether the patient is going to develop AIDS or not within the next time.
Consequently, there exists a need in the art for a reliable and quick diagnostic tool to reliably predict the onset of the disease.
The development of an HIV infection in the human body is in general determined by two interacting factors. The unique property of HIV to weaken the infected individual's immune system and the immune response of the host against the invader, which develops along with the infection's progress.
Prior to the development of the profound immunodeficiency status the immune system still performs its task to a certain extent producing particular molecules that may be detected in the infected individual long before the various conditions described above are perceived. It was therefore considered to use such molecules for the determination of the disease.
Molecules, which are presently used for this purpose, are e.g. &bgr;-microglobulin or neopterin. The use of these compounds for the determination of the disease suffers, however, from the fact that they are not particularly specific for an HIV infection and that they have to be prepared from blood samples in a complicated manner, which impedes the procedure of diagnosis. Further, the increase in the amount of those molecules in body fluids can only be determined at a stage at which other immune system parameters and virological assays already clearly indicate the development of AIDS.
Therefore, the problem underlying the present invention is to provide a novel diagnostic tool for predicting the onset of AIDS already at an early developmental stage of the disease, preferably already during predromal AIDS conditions.
The above problem has been solved by using a particular compound to be found in body fluids, the urinary trypsin inhibitor, as a diagnostic tool, and identifying its amount in said body fluids.
During the extensive experiments leading to the present invention it has been found that the amount of urinary trypsin inhibitor (UTI), which may ordinarily be present in a healthy person in the urine in an amount of up to about 3 &mgr;g/ml is markedly increased in patients suffering from an HIV infection in whom the disease is just about to develop.
Thus, according to the present invention there is provided the use of UTI in the diagnosis of the onset of AIDS, wherein the amount of UTI in a body fluid sample of an AIDS patient is determined, which body fluid may be blood or preferably urine. If the amount exceeds a certain level, in the urine 3 &mgr;g/ml, this may be taken as a reliable signal that this patient will develop the disease.
The amount of UTI in a body fluid may be determined according to methods known in the art, such as by means of antibodies, that may be polyclonal or monoclonal antibodies or an antibody containing serum. Other methods of UTI determination include measurement of the antitryptic activity or antichymotryptic activity in the sample.
The present invention also provides a kit for carrying out the determination of UTI-level in a body fluid sample, providing all the necessary ingredients and buffers for performing the assay.
REFERENCES:
patent: 5504065 (1996-04-01), Hattori et al.
patent: 0 371 706 A1 (1989-11-01), None
Koito et al., “A Neutralizing Epitope of Human Immunodeficiency Virus Type 1 Has Homologous Amino Acid Sequences With Active Site of Inter-Alpha-Trypsin Inhibitor,”International Immunology, 1(6):613-618(1989)(abstract only).
Kuwajima et al., “Automated Measurement of Trypsin Inhibitor in Urine with a Centrifugal Analyzer: Comparison with Other Acute Phase Reactants,”Clinical Biochemistry, 23(2):167-171 (1990) (abstract only).
Kuwajima et al., “Urinary Tryspin Inhibitor as an Acute Phase Reactant,”Japanese Journal of Clinical Pathology, 40(7):751-755 (1992) (abstract only).
Ogloblina et al., “Monoclonal Antibodies that Recognize Trypsin Binding Domain of Human Urinary Trypsin Inhibitor,”Hybridoma, 12(6):745-754 (1993) (abstract only).
Leary Louise
Nixon & Peabody LLP
Technologie Integrale Limited
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